1. Field of the Invention
The present invention relates to the noninvasive detection and measurement of small molecule substances that have passively diffused through the skin such as, for example, the noninvasive detection and measurement of glucose that has passively diffused through the skin, and more specifically the extrapolation of in vivo concentrations of the small molecule substance based on the amount of the small molecule substance that has diffused through the skin.
2. Background of the Related Art
The standard of care for determining an in vivo concentration of a host of small molecule substances (e.g., glucose) is by sampling venous blood for analysis in the lab, or by sampling a small volume of blood from a prick on the skin for point-of-care (POC) devices. The former requires the ambulatory patient to visit the doctor's office or the lab for a phlebotomy. Results can take up to several days. The latter is exemplified by the commercial glucometer where the patient himself administers the test at home or the nurse administers the test on the patient by the hospital bedside. Results can be obtained almost immediately. In both cases, however, a break in the skin is necessary which results in varying degrees of discomfort as well as potential exposure to infections.
In low birth weight (LBW) infants, the adverse effects of these kinds of tests are even more exaggerated. Pain causes undue distress on infants resulting in not only short term but also long term consequences, such as the development of abnormal response to pain in some children. The inherent low blood volume of extremely LBW infants means multiple blood withdrawals could result in anemia or might require blood transfusions. The potential for exposure to infections is therefore magnified.
Glucose is the main energy source for a neonate to survive and develop normally. At birth, clamping the umbilical cord interrupts the continuous transplacental transfer of glucose and other nutrients, and the newborn infant must mobilize its surge in the levels of circulating epinephrine, norepinephrine, and glucagon and a fall in insulin levels. These hormones concomitantly mobilize hepatic glycogen and stimulate gluconeogenesis, resulting in a steady rate of glucose production and maintenance of the plasma glucose concentration. However, when stressors such as maternal diabetes, preterm birth, temperature stress and infection disrupt this delicate balance, hypoglycemia or hyperglycemia can result. Both extremes of blood glucose in newborns pose significant challenges in the clinical management of the sick infant, requiring careful and vigilant monitoring to minimize impact on infant morbidity and mortality.
Hypoglycemia is the most common metabolic problem in neonates, occurring in as many as 5-15% of normal newborn infants and as high as 73% in the high-risk intrauterine growth restricted (IUGR)/small for gestational age (SGA) preterm infants. Although the absolute definition or value of hypoglycemia has been debated, most clinicians agree that serum glucose of less than 35-45 mg/dL defines neonatal hypoglycemia. Glucose is the primary energy substrate for the developing brain, therefore, it is imperative to monitor serum glucose frequently in the preterm population to promptly detect and treat neonatal hypoglycemia. Signs of hypoglycemia include hypotonia, bradycardia, hypothermia, lethargy, and poor feeding. However, the greatest concerns that can develop from significant, prolonged, and/or recurrent episodes of hypoglycemia are seizures and associated short and long-term neurodevelopmental impairments or death.
Hyperglycemia is less frequently observed in full term newborn infants than hypoglycemia, but is the most commonly observed perturbation of glucose metabolism in low birth weight (LBW) infants in the neonatal intensive care units (NICUs). Among extremely low birth weight (ELBW) infants, the incidence of neonatal hyperglycemia is estimated to be 45-80%. Like hypoglycemia, the exact definition in newborns remains unclear. However, a serum glucose level >125 mg/dL in term infants and >150 mg/dL in preterm infants can be considered hyperglycemic.
Because hyperglycemia is also associated with increased neonatal morbidity and mortality, this condition needs to be closely and carefully monitored. Hyperglycemia increases blood osmolarity and may cause electrolyte disturbances, osmotic diuresis, and the associated loss of electrolytes in the urine and has been associated with retinopathy of prematurity (ROP) and intra-ventricular hemorrhage (IVH). In addition, hyperglycemia also causes alterations in the immune response in the already immune-compromised premature infants. In certain circumstances, insulin therapy may have to be initiated in a hyperglycemic infant, at which point that infant would require more frequent glucose testing to monitor therapy and to prevent hypoglycemia.
The current standard of care for determining glucose levels from an infant is either by a point of care testing (POCT) bedside glucose analyzer and/or with one of the laboratory enzymatic methods. In either situation, the infant would have to be subjected to painful and invasive blood sampling, either from an arterial/venous draw or a heel lance to obtain the blood for testing. Premature infants who are already immune-compromised from an immature immune system are placed at greater risk of developing infections from either the blood draw process, by breakage of the skin, or from transfusion-acquired infections since blood sampling often necessitates blood transfusions to correct the anemia. Furthermore, subjecting these infants to painful procedures show that such procedures alter the pain perception of the infants long-term with long-term outcomes. Therefore, a non-invasive method for monitoring glucose would be a break-through in the medical management of sick, premature infants who are currently subjected to multiple blood draws.
Another problem is that currently available glucose analyzers were developed for adults. Less than 70 mg/dl blood glucose is considered hypoglycemic in adults, while in neonates it is <35 to 45 mg/dl. Thus, the limits by which clinical decisions need to be made for neonates are generally at the limits of accuracy and sensitivity of these analyzers. What may be considered acceptable sensor sensitivity for adults could overlook at risk neonates, leading to adverse consequences. Additionally, some of these glucose analyzers suffer from interference from the high oxygen, high bilirubin and high hemoglobin levels common in preterm infants. Thus, there are challenges on multiple fronts to designing an appropriate glucose sensor for neonates.